In general, nanoparticles have a variety of unique properties due to their extremely large specific surface area and surface activity, which derive from their small particle size. This has made it possible to create new materials not available in the past, and there has been much practical research in a variety of fields. Attention has focused in particular on such fields as electronics, coatings, cosmetics and drugs.
However, nanoparticles are difficult to mix uniformly at the primary particle level. Because of their extremely low bulk density, they are difficult to store and transport. Because they are highly reactive, moreover, they may cause dust explosions during mixing and other operations. Nanoparticles also have extremely poor fluidity due to their tendency toward adhesion and aggregation with each other. Another problem is that it is generally difficult to granulate nanoparticles that are hydrophobic and have static properties.
To resolve these problems, Japanese Patent Application Laid-open No. 2003-275281 discloses a method for producing drug-containing composite particles that have improved handling properties while retaining the advantages of nanoparticles, and which are particularly applicable to various pharmaceutical products including drug delivery systems (DDS).
Using the method disclosed in this Japanese Patent Application, at least one of a drug and a biocompatible polymer is made into nanoparticles with a mean particle size of less than 1000 nm, and a mixture comprising these nanoparticles is then processed into a composite by fluidized bed dry pelletization or dry mechanical particle composite processing to produce polymer nano-composite particles. Drug-containing composite particles are thereby produced which have been improved in handling without sacrificing the advantages of nanoparticles, and can be applied favorably to powder transpulmonary preparations and other drug delivery systems.
In the method described in this Japanese Patent Application, aqueous solutions of various biocompatible polymers are used as binders in the specific method of fluidized bed dry pelletization used to process a mixture containing nanoparticles into a composite, and nanoparticles (particles with a mean particle size of less than 1000 nm) are dispersed and suspended in this aqueous solution to produce a liquid raw material which is then sprayed inside a fluidized bed to form micro-sized composite particles.
However, this method uses large amounts of energy to evaporate large amounts of dispersion medium (water in the examples). Moreover, a foreign substance is introduced into the body in this method, even though the polymer used as the binder is biocompatible. Another problem is that because the polymer functions as a binder, it is difficult to subsequently disintegrate and re-disperse the nano-particles.
Moreover, in the other method used to process a mixture containing nanoparticles into a composite in this Japanese Patent Application, dry mechanical particle composite processing, nanoparticle aggregates (0.01 to 500 μm) prepared by the aforementioned method for example are affixed by compression or shearing force to the surface of carrier particles which are larger than the aggregates to thereby form composite particles. It is also described that adhesion between the carrier particles and nanoparticle aggregates is controlled by smoothing the surfaces of the carrier particles in advance or fixing lubricating particles to the surfaces of the carrier particles.
However, because strong compression or shearing force is applied to the nanoparticle aggregates in this method, they may be contaminated due to wearing of the machinery or adhere to the container or the like. The carrier particles also need to be removed for use, but there is no guarantee that they can be reliably removed.
The present invention was devised in light of these problems of prior art to improve the handling properties of nanoparticles. It is an object of the present invention to provide a method capable of granulating fine particles by an extremely easy operation without using carrier particles that cannot be reliably separated and removed or binders that remain as foreign material. Another object is to provide a method of granulating fine particles capable of providing a granulated product that can be rapidly and easily broken down into primary particles.